Reflex Syncope (Neurally Mediated Syncope)
Reflex syncope (synonym: neurally mediated [reflex] syncope) refers to a reflex response that, when triggered, gives rise to vaso-/venodilatation and/or bradycardia; however, the contribution of each of these two factors to systemic hypotension and cerebral hypoperfusion may differ considerably among affected individuals and may even differ in the same patient at different times. Since all forms of reflex syncope share essentially the same basic pathophysiology (i.e., they basically represent the same disorder as best as we currently understand), the apparent clinical differences only reflect primarily which specific trigger elicits the reflex.
KeywordsCarotid Sinus Structural Heart Disease Prodromal Symptom Cardiac Pace Vasovagal Syncope
11.1 Key points
Reflex (neurally mediated) syncope has a unique pathophysiological mechanism (i.e., a reflex response that, when triggered, gives rise to vasodilatation and/or bradycardia), but there are various clinical presentations, mostly age related.
There are two diagnostic goals: (1) to identify the etiology (i.e., differentiate reflex from other forms of syncope) and (2) to identify the mechanism of the reflex (i.e., to measure the relative contributions of vasodepression and bradycardia/asystole in causing syncope).
Therapy consists of general measures which are in common with all forms of reflex syncope, as well as specific therapies which are guided by the knowledge of the mechanism of the reflex.
In general, education and reassurance are sufficient for most patients. Modification or discontinuation of hypotensive drug treatment (if medically possible) for concomitant conditions is another first-line measure for the prevention of syncope recurrences. Treatment is not necessary for patients who have sustained a single/rare syncope/s and are not having syncope in a high-risk setting (i.e., commercial drivers, pilots).
Non-pharmacological “physical” treatments (counterpressure maneuvers and so-called tilt or standing training) are now the new first-choice therapies for neurally mediated reflex syncope.
There is evidence and general agreement that cardiac pacing is useful in cardioinhibitory or mixed carotid sinus syndrome and in some older patients with documented asystolic reflex syncope of the vasovagal type.
Advice to encourage increased fluid and salt intake for recurrent reflex fainters seems to be well supported clinically and by one randomized study, but has not yet been subjected to rigorous outpatient evaluation.
The evidence fails to support the efficacy of beta-blocking drugs. Beta-blocking drugs may aggravate bradycardia in some cardioinhibitory cases.
The role of fludrocortisone is currently undergoing randomized controlled study.
To date there are not sufficient data to support the use of any other pharmacological therapy for vasovagal syncope, although vasoactive agents such as midodrine have found some support in the literature.
11.2 The Wide Clinical Spectrum of a Unique Disorder
Reflex syncope (synonym: neurally mediated syncope) refers to a reflex response that, when triggered, gives rise to vaso-/venodilatation and/or bradycardia; however, the contribution of each of these two factors to systemic hypotension and cerebral hypoperfusion may differ considerably among affected individuals and may even differ in the same patient at different times. Since all forms of reflex syncope share essentially the same basic pathophysiology (i.e., they basically represent the same disorder as best we currently understand), the apparent clinical differences only reflect primarily which specific trigger elicits the reflex.1,2
There is an overabundance of names for reflex syncope, and this has proved confusing.1,2 For example, “neurogenic” has been used as a synonym for “reflex syncope,” but there is no compelling utility to this term. “Vasovagal syncope” is best reserved for a specific form of reflex syncope (see later), but some sources appear to consider it as a synonym for the broad range of reflex faints. We do not believe that the latter is appropriate and would prefer that the term “vasovagal” be reserved for the specific form of reflex faint that occurs in the setting of emotional distress or that occurs in the absence of a specific identifiable trigger. The descriptor common faint is appropriate as a synonym of vasovagal as it has an epidemiological basis, since vasovagal syncope is the most frequent form of syncope in the population up to the age of 60 (i.e., the word “common” refers to frequency in this case and does not imply simplicity). Other names that are commonly used in publications to depict “reflex syncope” include neurocardiogenic and neurally mediated cardiac. Neurocardiogenic, as a synonym for reflex syncope, has the disadvantage that it emphasizes cardiac effects while ignoring the vasodepressor contribution. Vasodepressor has also been used as an alternative for vasovagal syncope, but has the disadvantage of emphasizing the fall in systemic vascular resistance that, while important, overlooks the cardiac element. The terminology in children is particularly confusing, in that pallid breath holding spells and reflex anoxic seizures concern reflex syncope in infants with pronounced cardioinhibition often leading to asystole. Neither name conveys that the entity in question is a form of reflex syncope. In the end, the Task Force on Syncope of the European Society of Cardiology recommended that the broad condition be termed reflex or neurally mediated syncope. Specific subsets can then be specifically identified (e.g., vasovagal and carotid sinus syndrome).
Classification of reflex (neurally mediated) syncope
• Vasovagal syncope (common faint)
– Mediated by emotional distress: fear, pain, instrumentation, blood phobia
– Mediated by orthostatic stress
• Situational syncope
– Cough, sneeze
– Gastrointestinal stimulation (swallow, defecation, visceral pain)
– Micturition (post-micturition)
– Others (e.g., laughing, brass instrument playing, and weightlifting)
• Carotid sinus syncope
• Atypical forms (without apparent triggers and/or atypical presentation)
Often, reflex syncope has an atypical presentation. The term atypical form is used to describe those situations in which reflex syncope occurs with uncertain or even apparently absent triggers. The diagnosis then rests less on history taking alone and more on the exclusion of other causes of syncope (absence of structural heart disease) and on reproducing similar symptoms with carotid sinus massage, tilt-table testing, or other tests. Eye-witness accounts should also be sought as they can be very helpful.
Prevalence of different forms of reflex syncope in two different clinical settings
Emergency department (a) (309 pts)
Syncope unit (b) (602 pts)
– Carotid sinus syncope
– Likely reflex
Differences in clinical features of isolated vasovagal syncope and the atypical forms of reflex syncope occurring in the elderly
Isolated vasovagal syncope
Other forms (atypical)
• Onset at a young age
• Otherwise healthy people
• Typical vasovagal prodromes/triggers
• Affects about 50% of all individuals
• 70% of population predisposed
• Strong stressor
• No genetic basis
• No evidence of autonomic involvement or
• Low risk of trauma
• Frequent spontaneous disappearance in
• Onset in old age
• Patients with cardiovascular or neurological
• Presentation without prodromes/atypical
triggers (“non-classical” form)
• Often diagnosed only after a positive head-up
• Overlap with carotid sinus syndrome
• Overlap with situational syncope
• Overlap with orthostatic hypotension or other
• High risk of trauma
• Sometimes progressively worsening over time
• Similar hypotension–bradycardia mechanism
• Similar rate of positive responses during tilt testing
• Similar rate of cardioinhibitory and vasodepressor forms during spontaneous syncope
An abnormal reflex plays a role in causing syncope in different clinical settings where more than one pathophysiological factor may contribute to the symptoms. For instance, in the setting of valvular aortic stenosis or left ventricular outflow tract obstruction, syncope is not solely the result of restricted cardiac output, but is in part due to inappropriate neurally mediated reflex vaso-/venodilatation and/or primary cardiac arrhythmias. Similarly, a neural reflex component (preventing or delaying vasoconstrictor compensation) appears to play an important role when syncope occurs in association with certain brady- and tachyarrhythmias.8, 9, 10
There are two diagnostic goals: (1) identify the etiology (i.e., differentiate reflex from other forms of syncope) and (2) identify the mechanism of the reflex (i.e., to measure the relative contribution of vasodepression and bradycardia/asystole in causing syncope).
11.4 Identifying the Etiology of Syncope
Diagnosis of reflex syncope is made by typical history or positive response to tests and exclusion of other competing diagnosis.1,2 The starting point for the evaluation is a careful detailed medical history. In many patients without heart disease a definite diagnosis can be made by the history alone without further testing. This is the case in “classic” forms of vasovagal and situational syncope. Under such circumstances, the diagnosis is readily established and treatment, if any, can be planned. However, the diagnostic value of the history decreases with advancing age of the patient. For example, in one study,3 history alone was able to define the diagnosis in 38% of patients aged <65 years but only in 9% of patients aged >65 years.
• History and physical exam
• Carotid sinus massage
• Tilt-table testing
• Implantable loop recorder (ILR)
• ATP test (adenosine test)
• Eyeball compression test (especially useful in teenagers)
• Valsalva maneuver
• External loop recorder and mobile cardiac outpatient telemetry [MCOT (USA)]
• Echocardiogram (if structural heart disease is a serious concern)
Minimal or no value
• Holter monitoring
• Head CT/MRI
Diagnostic criteria of the different forms of reflex (neurally mediated) syncope
• Vasovagal syncope is diagnosed if syncope is precipitated by emotional distress (fear, severe pain, instrumentation, or blood phobia) or prolonged standing and is associated with typical prodromes due to autonomic activation. Under such circumstances, no further evaluation of the disease or the disorder may be needed
• Situational syncope is diagnosed if syncope occurs during or immediately after micturition, defecation, coughing, swallowing, laughing, meal, or immediately after the end of an exercise. Under such circumstances, no further evaluation of the disease or disorder may be needed
• Carotid sinus syncope is diagnosed if syncope is reproduced by carotid sinus massage in the presence of asystole >3 s and/or fall in systolic blood pressure >50 mmHg and in the absence of competing diagnoses
• Atypical form is diagnosed if syncope occurs without apparent triggers and/or has an atypical presentation and the diagnosis is based on the reproduction of similar symptoms by means of tilt testing (and ATP test) and on the exclusion of other causes of syncope (absence of structural heart disease)
• Likely reflex (neurally mediated) is diagnosed if the history suggests a reflex cause, unconfirmed by tests, structural heart disease was absent, and other causes can reasonably be excluded; or syncope is the first (or rare) episode, structural heart disease is absent, and other causes can reasonably be excluded
11.4.1 Vasovagal Syncope
There are two main triggers for vasovagal syncope: (1) central and (2) peripheral. Among the central triggers, emotion, pain, and instrumentation are the most frequent. With respect to the peripheral triggers, standing is particularly important, especially when it is associated with a hot/crowded environment, exercise, dehydration, illness, or excessive alcohol consumption. However, prolonged standing alone may provoke vasovagal syncope (i.e., even in the absence of other contributing factors), especially if the individual is standing very still (e.g., guards in front of prominent buildings). Most vasovagal episodes are probably triggered by peripheral triggers.
In some subjects, the range of triggers varies widely, including syncopal attacks without any trigger at all. In such cases the presence of typical vasovagal attacks in the same individual’s history allows atypical attacks to be accepted as vasovagal, more so than when no typical attacks have ever occurred. In orthostatic vasovagal syncope, the triggering pattern differs from that in orthostatic hypotension due to autonomic failure. In the first, syncope or presyncope occurs very rarely compared to the number of times the subjects stand; syncope may occur after a highly variable time of standing and sets in quickly when it occurs. In autonomic failure, blood pressure usually drops immediately and consistently after standing up; the blood pressure drop may be measured, even though symptoms may not occur at the time.
220.127.116.11 Autonomic Activation
Vasovagal syncope is usually preceded by autonomic activation: intense pallor (“white as a sheet”), sweating, and nausea are most common. Prodromal symptoms usually start 30–90 s before syncope. A feeling of warmth, an odd sensation in the abdomen, and light-headedness or dizziness may be mentioned in addition to nausea and sweating. Eyewitnesses may notice pallor and wide pupils. After syncope, autonomic activation may continue a while, and vasovagal syncope may reoccur if the triggers are not removed. Although consciousness recovers quickly without confusion in adults, patients may be upset and experience pronounced fatigue after syncope (often lasting many hours).
As a consequence of the above findings, vasovagal syncope can be diagnosed if the syncope is precipitated by emotional distress (fear, severe pain, instrumentation, or blood phobia) or prolonged standing and is associated with typical prodromes due to autonomic activation. No further evaluation is needed unless there are other clues to important concomitant conditions that on rare occasion may be responsible for triggering a vasovagal faint (e.g., inferior wall myocardial infarction, temporal lobe epilepsy).
11.4.2 Situational Syncope
Situational syncope traditionally refers to reflex syncope associated with certain specific circumstances, which act as the trigger. The various forms have the efferent reflex syncope pathway in common, but obviously differ in terms of the afferent triggers. Several authors compared situational syncope with vasovagal syncope; people with situational syncope tended to be older and more often had pronounced prodromal symptoms and signs.
Situational syncope is less common than vasovagal syncope. Specific forms are diagnosed if syncope occurs during or immediately after micturition, defecation, coughing, swallowing, laughing, eating, or immediately after vigorous exercise.1,2 Under such circumstances, no further evaluation is needed.
18.104.22.168 Cough (Tussive Syncope)
Cough (tussive syncope) is evoked by coughing.15,16 Cough syncope occurs during bouts of intense coughing without prodromal symptoms, usually in heavy-built, obese, middle-aged smoking men with chronic obstructive pulmonary disease. Attacks may occur not only while standing and sitting (e.g., driving) but also while lying down. The pathophysiology remains incompletely understood. Consequently, it is uncertain whether cough syncope should be considered a form of syncope mostly due to mechanical factors (high intra-thoracic pressure transmitted to veins resulting in such a high intracranial pressure that there is no longer a pressure gradient, i.e., no perfusion pressure) or to a reflex (baroreflex hypotensive response to very high transient blood pressures induced by the cough or the stimulation of pulmonary or atrial receptors during coughing).
22.214.171.124 Swallow (Deglutition Syncope)
Swallow (deglutition) syncope, as the name suggests, is induced by swallowing.17 Presyncope and syncope follow swallowing almost immediately in this condition. Swallow syncope may occur at any age, although most case reports concern those of middle age or older. It may occur only after specific foods, which may be solids, liquids, or carbonated drinks; either hot or cold drinks can elicit syncope. In others, syncope can occur independently of the nature of the food item. In reported cases the mechanism is almost always through either cardioinhibition with sinus bradycardia or asystole, or AV block. Swallow syncope occurs either in healthy subjects or in patients suffering from esophageal or cardiac disease; how esophageal pathology triggers the reflex is not known, but bradycardia following balloon inflation of the esophagus implicates mechanoreceptors. Atropine can block bradycardia, making it clear that the efferent arc is vagal in nature.
126.96.36.199 Micturition (Post-micturition)
Syncope occurs during or immediately after emptying the bladder. It typically occurs in men who get up from sleep at night to go to the bathroom. They faint either at the toilet or shortly after leaving the bathroom. It is much less common in women. Micturition syncope probably represents a reflex “helped along” by various circumstances: subjects may arise from sleep, suggesting low nocturnal blood pressure and peripheral vasodilatation due to lying in a warm bed. Standing still during micturition allows pooling of blood without counteraction by the leg muscle pump. Finally, voiding the bladder triggers the syncopal reflex. A complex mechanism entailing a balance between the hypertensive effect of a full bladder and the compensating vasodilatory baroreceptor action has been hypothesized. When the bladder is abruptly emptied, the hypertensive reflex is terminated but the vasodilation persists just long enough to trigger a collapse.
188.8.131.52 Defecation Syncope
Defecation syncope occurs during or shortly after defecation.18 It is likely that defecation syncope results from multiple influences. One factor may be getting up out of a warm bed. Additionally, straining at stool involves multiple repeated Valsalva maneuvers which may impede cardiac venous return and cerebral blood flow. Finally, pressure in the colon may evoke a true reflex syncope, evidenced by bradycardia and low blood pressure during colonoscopy.
184.108.40.206 Post-exercise Syncope
Post-exertional syncope19,20 is almost invariably due to autonomic failure or to a neurally mediated mechanism and is characterized by hypotension which can be associated with marked bradycardia or asystole; it typically occurs in subjects without heart disease, especially in athletes. Rarely, as has been discussed earlier in this volume, reflex syncope can also occur during exercise; in this latter case, it is caused by marked hypotension without bradycardia. It has been supposed that epinephrine plays an important role in the mechanisms leading to neurally mediated syncope associated with exercise. A failure of reflex vasoconstriction in splanchnic capacitance vessels and in forearm resistance vessels has been shown during exercise in patients with vasovagal syncope. Tilt-table testing has been used to diagnose neurally mediated syncope, which may manifest as post-exertional syncope; however, it is not a very reliable way of reproducing the phenomenon in these very select and physically fit patients.
220.127.116.11 Post-prandial Syncope
Post-prandial hypotension is a prevalent condition in the elderly population and seems to be more common in frail elderly individuals who may be particularly susceptible to complications such as syncope.21,22 The diagnosis is based on the measurement of meal-induced blood pressure changes. The precise relationship between symptoms and post-prandial reductions in blood pressure is unclear. Blood pressure maintenance after a meal may depend on the interaction of sympathetic function, baroreceptor function, and vasoactive peptide release to compensate for the increase in bowel blood volume. The impairment of one or more of these mechanisms could result in inadequate compensation that leads to hypotension and syncope. The presence of symptoms depends on the individual patient’s ability to develop adequate compensatory cerebral autoregulation. A hypertensive elderly patient may experience symptoms with only a small reduction in blood pressure. Thus, the mechanism of post-prandial syncope could be similar to that of vasovagal syncope triggered by orthostatic stress.
18.104.22.168 Laughter (Gelastic) Syncope
Laughter (gelastic) syncope is elicited by laughter.23 Very few cases have been described and the differentiation from cataplexy attacks (which are also often associated with laughter) is important (but difficult). Prolonged hearty laughter triggers the episode, without prodromal symptoms. In one case, Valsalva maneuver showed a drop in blood pressure at the end of the maneuver with unconsciousness. In some cases, tilt-table testing resulted in a vasovagal response, suggesting susceptibility to reflex syncope. The mechanism could be similar to that of cough syncope. The triggering by laughter may suggest cataplexy, but laughter syncope causes amnesia for the event, which is not typically the case in cataplexy.
22.214.171.124 Sleep Syncope
In sleep syncope, sleep is the circumstance which characterizes this form of reflex syncope, but is not its trigger.24,25 The patients, mostly middle-aged women, give a history of waking from sleep with either abdominal discomfort or the urge to defecate followed by syncope. In some, syncope occurs in bed, in others while trying to get to the toilet. Some patients remember nightmares before the episode. Most patients also have daytime episodes, which sound vasovagal in nature. Tilt-table testing is frequently positive. When ECG documentation could be obtained, a typical vasovagal pattern has been observed. In the differential diagnosis of nocturnal syncope, epilepsy is probably the foremost alternative diagnosis, but cardiac arrhythmias need careful consideration as well.
11.4.3 Carotid Sinus Syncope
The prevalence of carotid sinus syndrome (CSS) increases with age, ranging from 4% in patients <40 years to 41% in patients >80 years among those referred to a specialized facility for syncope of uncertain origin. It is more frequent in men than in women with a 4:1 ratio.26,27
In its rare spontaneous form, CSS is believed to be triggered by mechanical manipulation of the carotid sinuses, either by external stimuli (e.g., tight collar) or by masses in the neck close to the sinuses (e.g., tumor and lymph nodes). Previous neck surgery and/or irradiation markedly increases susceptibility to CSS. In the more common form of CSS, no evident mechanical trigger is identified; the condition is diagnosed by carotid sinus massage and it is called induced carotid sinus syndrome.1,2 Spontaneous carotid sinus syncope should therefore be considered as a form of situational syncope as, by definition, a specific trigger has been identified.
Unlike vasovagal syncope, in CSS there are no clear signs of autonomic activation. Prodromes are usually absent or non-specific and of short duration; recovery is usually prompt. CSS occurs mostly while the patients are standing. Owing to its unpredictability and its occurrence in the elderly, major trauma (defined as bone fracture, intracranial hemorrhage, internal organ lesions requiring urgent treatment, and retrograde amnesia or focal neurologic defect) is more frequent than in other patients with syncope.
There are several diseases that predispose to carotid sinus syndrome. These are atherosclerosis, coronary artery disease, head and neck surgery/irradiation, acute biliary tract disturbances, diabetes, and some drugs such as digitalis and beta-blockers. Moreover, carotid sinus syndrome is frequently associated with sinus node dysfunction (from 21 to 56% in various surveys) and with AV conduction abnormalities (from 21 to 37% in various surveys). Patients affected by CSS are expected to have recurrence of syncope (about 50% at 2 years) and minor symptoms (about 2/3 of affected individuals at 2 years). Carotid sinus syndrome is associated with a high mortality (about 35% at 5 years) but this mortality seems to be related to associated comorbidities and older age rather than to the syndrome itself.28
In practice, the diagnosis of induced CSS virtually coincides with that of positive carotid sinus massage. Carotid sinus hypersensitivity is present in many subjects who have not yet manifested the clinical syndrome, i.e., syncope. It is well known, for example, that abnormal responses are frequently observed in 17–20% of asymptomatic patients affected by various types of cardiovascular diseases and in 38% of asymptomatic patients with severe narrowing of the carotid arteries. However, in asymptomatic subjects, the induction of syncope is much less frequent so that the specificity of the test increases if reproduction of spontaneous syncope during carotid massage is required. In other words, the potential number of patients who might suffer from CSS is higher than those who have actually manifested it. Nevertheless, from a practical point of view, a positive response to carotid massage should be considered diagnostic of the cause of syncope only in patients with a high likelihood of CSS as identified in the initial evaluation. Indeed, when competitive diagnoses for the cause of syncope are still present, the finding of a positive carotid sinus massage must be viewed with caution. In these cases, other tests are needed to confirm the mechanism of syncope (i.e., ECG documentation by prolonged monitoring). Therefore, CSS is diagnosed only if syncope is reproduced by carotid sinus massage in the presence of asystole >3 s and/or fall in systolic blood pressure >50 mmHg and in the absence of competing diagnoses1, 2 (see Chapter 7).
11.4.4 Atypical Forms (Without Apparent Triggers and/or Atypical Presentation)
Atypical forms of reflex syncope are diagnosed if syncope occurs without apparent triggers and/or has an otherwise unusual presentation. The diagnosis is based on the reproduction of similar symptoms by means of tilt-table testing29 and/or ATP test (the atypical form diagnosed by carotid sinus massage is classified as carotid sinus syncope) and on the exclusion of other causes of syncope (e.g., absence of structural heart disease) (see Chapter 7). Atypical forms are the most frequent cause of reflex syncope among the elderly and patients referred to specialized syncope facilities (Table 11.2). Atypical forms are frequently associated with cardiovascular or neurological disorders and other dysautonomic disturbances (Table 11.3). The absence of a clear history and the possibility of multiple etiologies make the diagnosis difficult to establish. Documentation of a spontaneous event by means of prolonged ECG monitoring is frequently necessary either for confirming the diagnosis or for starting mechanism-specific treatment.
In patients without structural heart disease, tilt-table testing can be considered diagnostic, and no further tests are needed when syncope is reproduced.1,2 In patients with structural heart disease, arrhythmias or other cardiac causes should be excluded prior to considering the positive tilt test results to be diagnostic. ATP testing produces an abnormal response in some patients with syncope of unknown origin, but only infrequently in controls. ATP testing identifies a group of patients (usually older women) with otherwise unexplained syncope with definite clinical features and benign prognosis but possibly heterogeneous mechanism of syncope. The clinical feature of adenosine (ATP)-sensitive patients is different from that of tilt-positive patients. Adenosine-sensitive patients are older with a female predominance, have a shorter history of syncope, and have a higher prevalence of systemic hypertension.
11.4.5 Likely Reflex (Neurally Mediated)
Reflex (neurally mediated) syncope is considered likely if the history suggests but is not definitive for a reflex cause (see historical features discussed above), the diagnosis has not been confirmed by tests, structural heart disease is absent, and other causes can reasonably be excluded; or syncope has occurred only one time or very rarely, structural heart disease is absent, and other causes can reasonably be excluded.1,2 These two situations are very frequent in clinical practice (Table 11.2). Since a certain diagnosis has not been made, syncope in these cases should be classified as “unexplained.” In general, these forms have a clinical presentation characterized by one or few episodes of syncope, usually preceded by warnings, not accompanied by trauma, and a benign outcome. For the above reasons, intensive evaluation (e.g., loop recorder implantation) is usually not justified unless the patient and/or the family is very concerned or there is a worrisome family history (i.e., unexplained sudden death). In the latter circumstance, an insertable loop recorder (ILR) is probably the best choice in order to ultimately capture a spontaneous episode.
11.5 Identifying the Mechanism of Syncope
Determining the relative contribution of vasodilatation and bradycardia/asystole to the hypotension causing syncope is of practical importance when the severity of the clinical presentation (because of high frequency or high risk of the episodes) justifies a specific treatment (i.e., cardiac pacing when the cardioinhibitory reflex is dominant and vasoactive measures when the vasodepressor reflex is dominant). Apart from this situation, the knowledge of the precise mechanism is less important as the two forms have similar outcome and share common preventive basic measures.
Value of different examinations in predicting the mechanism of the spontaneous reflex
Prolonged ECG monitoring
No documentation in about a half of patients up to a 2-year period
Carotid sinus massage
Only if syncope is reproduced by massage
With the possible exception of asystole occurring during tilt testing
ATP test (adenosine test)
Further study is needed. May play a role in patients with idiopathic paroxysmal AV block
11.5.1 ECG Monitoring
ECG monitoring is diagnostic when a correlation between syncope and ECG abnormality (brady- or tachyarrhythmia) is detected. Conversely, ECG monitoring excludes an arrhythmic cause (but not a vasodepressor cause) when syncope occurs in the absence of a clinically significant rhythm variation; in this case a dominant vasodepressor form can be hypothesized but cannot be said to be established. Pseudosyncope is still a consideration. Even in the absence of syncope–ECG correlation, ECG monitoring is currently deemed diagnostic if major arrhythmias are detected (periods of Mobitz II- or III-degree AV block or a ventricular pause >3 s, rapid prolonged paroxysmal atrial or ventricular tachyarrhythmias). Conversely, presyncope may not be an accurate surrogate for syncope in establishing a diagnosis in the absence of such arrhythmias and, therefore, therapy should not be guided by presyncopal findings. See also Chapter 8.
11.5.2 Carotid Sinus Massage
The relationship between induced carotid sinus syndrome (i.e., reproduction of syncope during the massage) and spontaneous, otherwise unexplained syncope was derived from one study30 using a pacemaker designed to detect asystolic episodes. Long pauses (≥6 s) were detected in 53% of the patients with CSS during 2 years of follow-up, suggesting that a positive response to carotid massage predicts the occurrence of spontaneous asystolic episodes. This correlation was recently confirmed by means of documentation of spontaneous episodes by an implantable loop recorder (ILR) in 18 patients affected by cardioinhibitory carotid sinus syndrome in whom carotid sinus massage was positive (maximum pause of 5.5 ± 1.6 s [range 3.6–8.5 s]).31 Asystole >3 s (average longest pause of 9 [8–18]s) was observed at the time of the spontaneous syncope in 16 (89%) patients. Sinus arrest was the most frequent finding and was observed in 72% of these cases. Moreover, the relationship between induced carotid sinus syndrome and spontaneous syncope is indirectly supported by the results of the studies on cardiac pacing in patients with cardioinhibitory forms which generally showed a reduction of syncopal relapses. Finally, when performed with a proper protocol, carotid sinus massage showed an excellent reproducibility. Thus, the type of response to carotid sinus massage is usually considered a good predictor of the spontaneous forms of the reflex syncope and consequently is in general sufficient to guide therapy (usually cardiac pacing) unless competing diagnoses are present. See also Chapter 7.
11.5.3 Tilt-Table Testing
The clinical significance of the type of response to tilt-table testing in predicting the behavior of blood pressure and heart rate during spontaneous syncope has recently been questioned. The reproducibility of a positive tilt test is low. The reproducibility of an initial positive response ranges in the literature from 31 to 92%. The relative contributions of vasodilatation and cardioinhibition components of hypotension during tilt-induced syncope are frequently different from those of spontaneous syncope recorded with the implantable loop recorder. In the ISSUE 2 study,32 while a positive cardioinhibitory response to tilt testing predicted an asystolic spontaneous syncope in a few cases, the presence of a positive vasodepressor or mixed response, or even a negative response, did not exclude the presence of asystole during spontaneous episodes. Thus, the type of response to tilt-table testing does not adequately predict the spontaneous forms of the reflex syncope; therefore, other tests (i.e., prolonged monitoring) are usually required before embarking on cardiac pacing therapy (the possible exception, as noted above, may be a tilt test that results in prolonged asystole in older patients). See also Chapter 7.
11.5.4 ATP (Adenosine) Test
The role of the ATP (Adenosine) test is controversial and there is substantial difference of opinion regarding its place in the evaluation of syncope patients. Initial studies supported potential pacing benefit if the test was positive, a recent study showed no correlation between AV block induced by ATP and ECG findings (documented by ILR) during spontaneous syncope. Thus, finding to date do not support its use as a solitary diagnostic test for selecting patients for cardiac pacing. ATP may, however, have a role to play in assessing syncope in middle-aged and older patients (especially women) with suspected paroxysmal AV block. See also Chapter 7.
Although there are different forms of reflex syncope, the strategies for prevention of syncope apply to most causes (carotid sinus syndrome may be an exception). Owing to its benign nature, the goal of therapy is primarily prevention of recurrence and associated injuries and improvement in quality of life but not prolongation of survival.
11.6.1 Lifestyle Measures
The cornerstone of the non-pharmacological management of patients with reflex syncope is education and reassurance regarding the benign nature of the condition. In this context, the term “benign” means “not directly life threatening.” However, recurrent faints may lead to injury and accidents. Consequently, it is crucial that the importance of preventive treatment be emphasized in discussion with patients, family members, and other caregivers.
In general, initial treatment comprises education regarding awareness and possible avoidance of triggers (e.g., hot crowded environments, volume depletion) and early recognition of prodromal symptoms.1,2 Eliminating exposure to triggers may be difficult, but the response may be attenuated by maintenance of central volume, protected posture, and slower changes in posture. Careful avoidance of agents that lower blood pressure (including beta-blockers, angiotensin-converting enzyme inhibitors, alpha-blockers, calcium antagonists, diuretics, antidepressant agents, and alcohol) is important. In younger patients, increased salt and volume intake is encouraged. Often, young persons restrict their salt intake excessively, and while this may have theoretical long-term health benefits, it may increase risk of reflex faints.
11.6.2 Additional Treatments
very frequent syncope alters quality of life,
recurrent syncope without or with very short prodrome exposes patients to risk of trauma,
syncope occurs during high-risk activity (e.g., driving, machine operation, flying, and competitive athletics).
11.6.3 Physical Counterpressure Maneuvers (PCM)
Non-pharmacological “physical” treatments are emerging as a new frontline treatment of reflex syncope (with the exception of carotid sinus syndrome). Two clinical trials33,34 have shown that isometric PCM of the legs (leg crossing) or of the arms (hand grip and arm tensing) are able to induce a significant blood pressure (BP) increase during the phase of impending reflex syncope that allows the patient to avoid or delay losing consciousness in most cases. The results have been confirmed in a multicenter prospective trial,35 which assessed the effectiveness of PCM in daily life in 223 patients, aged 38 ± 15 years, with recurrent reflex syncope and recognizable prodromal symptoms: 117 patients were randomized to standardized conventional therapy alone, and 106 patients received conventional therapy plus training in PCM. The median yearly syncope burden during follow-up was significantly lower in the group trained in PCM than in the control group (p < 0.004); overall 51% of the patients with conventional treatment and 32% of the patients trained in PCM experienced recurrence of syncope (p < 0.005). Actuarial recurrence-free survival was better in the treatment group (logrank p < 0.018), resulting in a relative risk reduction of 39% (95% confidence interval, 11–53%). No adverse events were reported.
Tilt-table testing can be employed to teach the patient to recognize early prodromal symptoms. All patients should be taught PCM, which now forms the cornerstone of therapy together with education and reassurance. However, this therapy is hampered by the fact that patients sometimes do not have recognizable prodromal symptoms or these are of too short duration to allow the activation of PCM. Moreover, the maneuvers are much less effective in female and in older patients because of diminished muscle strength and slower response time, and associated diseases.
As a rule, syncope burden dramatically decreases after starting PCM, but syncope sometimes recurs in a substantial percentage of patients, approximately 20% per year.36,37 A practical description of how to train patients is given in Chapter 21. In patients who continue to faint despite adequate lifestyle measures and PCM, “tilt training” (also known as “standing training”) may be considered, particularly in younger, very symptomatic, well-motivated patients. Despite controversy regarding efficacy, tilt training may prove useful and at the very least helps by reassuring the patient that they are active participants in the treatment.
11.6.4 Tilt Training (Standing Training) Method
In highly motivated young patients with recurrent vasovagal symptoms triggered by orthostatic stress, the prescription of progressively prolonged periods of enforced upright posture may reduce susceptibility to syncope recurrence.37 However, this treatment is hampered by the low compliance of patients in continuing the training program for a long period and four small randomized controlled trials failed to confirm short-term effectiveness of tilt training.38, 39, 40, 41
11.6.5 Pharmacological Therapy
Many drugs have been tested in the treatment of reflex syncope; for the most part the results have been disappointing.42, 43, 44, 45, 46 The list includes beta-blockers, disopyramide, scopolamine, theophylline, ephedrine, etilefrine, midodrine, clonidine, and serotonin reuptake inhibitors. While results have been satisfactory in uncontrolled trials or short-term controlled trials, several long-term placebo-controlled prospective trials have been unable to show a benefit of the active drug over placebo with some exceptions.
Beta-blockers have been advocated in vasovagal syncope based on presumed lessening of ventricular mechanoreceptor activation owing to their anti-sympathetic and negative inotropic effects in reflex syncope. This theory has not been supported by the outcome of one major clinical trial (POST45). A rationale for use of beta-blockers in other forms of neurally mediated syncope is lacking. They may enhance bradycardia in carotid sinus syndrome. Beta-blockers have failed to be effective in five of six long-term follow-up studies.42, 43, 44, 45, 46
Since failure to achieve proper vasoconstriction of the peripheral vessels is common in reflex syncope, alpha agonist vasoconstrictors (etilefrine and midodrine) have been used. Two double-blind, acute tilt studies have shown apparent contrasting effects. Moya et al.47 administered etilefrine for 1 week, then repeated the test and found no difference between active and placebo treatment. On the contrary, Kaufman et al.48 administered a single dose of midodrine just 1 hr before tilt testing and found a significant reduction in syncope during tilt with active treatment. Etilefrine was studied in a large randomized placebo-controlled, double-blind clinical trial.49 During follow-up, patients treated with etilefrine 25 mg twice daily or placebo showed no difference in frequency or time to recurrent syncope. Thus, the evidence fails to support the use of etilefrine. Midodrine was studied in three small, open-label, randomized trials in patients affected by very frequent “hypotensive” symptoms (>1 syncope/month).50, 51, 52 Even if defined as “neurally mediated,” there is overlap in clinical features of patients in these studies with other forms of orthostatic intolerance rendering the results difficult to interpret. The major limitation of midodrine is frequent dosing (2–3 times daily), which may limit long-term compliance. Caution must be taken in the use of midodrine in older males because of adverse effects on urinary outflow. Overall, these data suggest that chronic pharmacological treatment with alpha agonists alone may be helpful but inadequate in reflex syncope; further, long-term treatment cannot be advised for occasional symptoms. Even if not proven, a self-administered single dose of midodrine, for example, 1 dose 1 h before prolonged standing or performing an activity that usually triggers syncope (the so-called pill in the pocket strategy), may be useful in selected patients when added to lifestyle measures and PCM.
Fludrocortisone has been shown to be ineffective in a small, randomized double-blind trial in children.53 Fludrocortisone has been widely used in adults with reflex syncope, but there is no trial evidence to support this. It is, however, currently being evaluated in a large randomized trial in adults (POST 2).
Paroxetine was shown to be effective in one placebo-controlled trial, which included highly symptomatic patients from one institution.54 This has not been confirmed by other studies. Paroxetine may reduce anxiety, which precipitates events. Paroxetine is a psychotropic drug requiring caution in use in patients without severe psychiatric disease.
11.6.6 Cardiac Pacing
126.96.36.199 Carotid Sinus Syndrome (CSS)
Pacing has been considered as the most important therapeutic option for CSS since the early 1970s when case reports demonstrated that recurrences of syncope were abolished after implantation of a pacemaker.55 Subsequent case series then confirmed that pacing in patients with CSS could significantly reduce the number of syncope episodes.56 Non-randomized comparative studies supported these preliminary results and in the mid-1980s, pacing became the recognized treatment of CSS.
Thus, cardiac pacing appears to be effective in CSS and is acknowledged to be the treatment of choice when bradycardia has been documented. Dual-chamber pacing is generally preferred over single-chamber ventricular pacing. There are as yet no randomized studies examining treatment of dominant vasodepressor CSS; this same limitation also pertains for other vasodepressor conditions.
188.8.131.52 Other Forms of Reflex Syncope
Pacing for reflex vasovagal syncope has been the subject of five major multicenter, randomized controlled trials, which gave contrasting results.59, 60, 61, 62, 63 In all the patients, the pre-implant selection was based on tilt-table testing response. Adding together the results of the five trials, 318 patients were evaluated: syncope recurred in 21% of the paced patients and in 44% of unpaced patients (p < 0.001). A recent meta-analysis of all studies suggested a non-significant 17% reduction in syncope from the double-blinded studies and an 84% reduction in the studies where the control group did not receive a pacemaker.64 The results are not surprising if we consider that pacing may affect the cardioinhibitory component of the vasovagal reflex, but will have no effect on the vasodepressor component, which is often dominant.
Two non-randomized trials evaluated the efficacy of pacing by selecting patients with documented asystole during spontaneous syncope by ILR. In the study of Sud et al.,65 after the insertion of a cardiac pacemaker, syncope burden decreased from 2.7 per year to 0.45 per year (p = 0.02). The ISSUE 2 study32 hypothesized that spontaneous asystole and not tilt test results should form the basis for patient selection for pacemaker therapy. This study followed 392 patients with presumed reflex syncope with an ILR. Of the 102 patients with a symptom–rhythm correlation, 53 underwent loop recorder-guided therapy, predominantly pacing for asystole. These patients experienced a striking reduction in recurrence of syncope compared with non-loop recorder-guided therapy (10% versus 41%, p = 0.002). It must be stressed that ISSUE 2 was not a randomized trial. It merely provides the basis for such a trial, now ongoing (ISSUE 3, the enrollment of which is complete but the follow-up phase in ongoing).
In conclusion, pacing plays only a small role in therapy for reflex syncope, unless severe spontaneous bradycardia is detected during prolonged monitoring (especially in older individuals).
Treatment of reflex syncope
Recommendations of the 2009 ESC Task Force on Syncope
•Explanation of the diagnosis, provision of reassurance, and explanation of risk of recurrence are indicated in all patients
•Isometric PCM are indicated in patients with prodrome
•Cardiac pacing should be considered in patients with dominant cardioinhibitory CSS
•Cardiac pacing should be considered in patients with frequent recurrent reflex syncope, age > 40 years, and documented spontaneous cardioinhibitory response during monitoring
•Midodrine may be indicated in patients with VVS refractory to lifestyle measures
•Tilt training may be useful for education of patients but long-term benefit depends on compliance
•Cardiac pacing may be indicated in patients with tilt-induced cardioinhibitory response with recurrent frequent unpredictable syncope and age > 40 after alternative therapy has failed
•Triggers or situations inducing syncope must be avoided as much as possible
•Hypotensive drugs must be modified or discontinued
•Cardiac pacing is not indicated in the absence of a documented cardioinhibitory reflex
•Beta-adrenergic blocking drugs are not indicated
11.7 Clinical Perspectives
Clear criteria for diagnosis of reflex syncope have been recently established in the ESC syncope practice guidelines. Application of these guideline recommendations should provide practicing physicians a solid basis for establishing whether a reflex faint underlies their patients’ symptoms. On the other hand, the therapeutic strategies for reflex syncope (especially vasovagal syncope), despite the advances of recent years, are still not completely satisfactory. Syncope recurrence rate remains high, being approximately 10% per year in the general population and even up to 40% in selected populations (see also Fig. 6.3). New therapeutic options are needed.
The efficacy of therapy is hampered by difficulty identifying the relative contributions of vasodepression and bradycardia/asystole in causing syncope in a given patient at a particular time; this distinction is important as it forms the basis for a mechanism-specific therapy. Whether a diagnostic strategy of extensive utilization of prolonged ECG monitoring, i.e., implantable loop recorders, could provide more insight in this regard is a matter for future research.
Cardiac pacing seems to be effective when a dominant cardioinhibitory reflex is documented (the best example being carotid sinus syndrome), but the coexistence of a vasodepressor reflex accounts for the failure of pacing to prevent all symptoms in some cases. In this regard, the difficulty of documenting blood pressure during spontaneous syncope is a major diagnostic problem and a challenge for future technological developments. On the other hand, no predictably effective therapies for the vasodepressor reflex yet exist. Even physical counter maneuvers, which are probably the most effective among current acute treatments, often fail to abort the attack because the patients are unable to activate them with sufficient force, or at all. This limitation most frequently happens when prodromes are absent or are of very short duration and in older patients because they have diminished muscle strength and difficulty reacting rapidly. No pharmacological therapy has been proven to be totally effective. Midodrine, a vaso-/venoconstrictor, is the most useful of currently available drugs but side effects often preclude aggressive dosing.